Kyoto University (京都大学) / 0048 / 新制・課程博士 / 博士(工学) / 甲第17572号 / 工博第3731号 / 新制||工||1569(附属図書館) / 30338 / 京都大学大学院工学研究科電気工学専攻 / (主査)教授 小林 哲生, 教授 土居 伸二, 教授 山川 宏 / 学位規則第4条第1項該当

Background. Major depressive disorder (MDD) is a leading cause of death and disability worldwide, and many individuals with MDD will experience treatment-resistant depression (TRD). TRD can lead to the development of suicidal ideation and behaviours, and up to 30% of people with refractory depression will attempt suicide at some point in their life. A neurobiological understanding of suicide is lacking, and neuroimaging markers of illness may elucidate the relationship between suicidal ideation and attempt. Diffusion tensor imaging (DTI) is a particularly sensitive neuroimaging modality that quantifies the microstructural integrity of white matter tracts, which may be useful in the investigation of psychiatric disease. The source of white matter changes may be further elucidated using free water imaging to isolate signal specific to the fibre tract and quantify the fractional volume of the free water compartment. Methodology. For this study, data were obtained from N=36 outpatients with TRD (n=20 suicide ideators and n=16 suicide attempters). Clinical characteristics of the patient sample were examined using clinician-rated and self-report questionnaires of depression and suicidal ideation severity. Whole-brain analysis of DTI data was conducted using tract-based spatial statistics (TBSS) via FMRIB Software Library (FSL) to identify between-group differences in white matter microstructure between suicide ideators and attempters. Free water imaging correction was applied through estimation of a constrained bi-tensor model via an in house MatLab-based script developed at Harvard University. Between-group differences of suicide ideators versus attempters were identified at a family-wise error (FWE) corrected significance threshold of p≤0.05. Subsequent exploratory analyses were performed at an uncorrected significance threshold of p≤0.01. Results. Suicide attempters had greater family history of suicide attempt, higher self-reported suicidal ideation severity, and were more likely to have received overnight treatment in a psychiatric facility in the past. TBSS revealed elevated mean diffusivity (MD), axial diffusivity (AD) and free water (FW) in suicide attempters compared to suicide ideators (thresholded p=<0.05, family-wise error corrected). Subsequent exploratory analyses revealed reduced fractional anisotropy (FA) and elevated radial diffusivity (RD) in fronto-thalamo-limbic white matter tracts of suicide attempters (thresholded p=<0.01, uncorrected). Free water correction appeared to increase detection of fractional anisotropy changes and suppress spurious differences in axial and radial diffusivity. Conclusion. The identification of significantly altered diffusion metrics in suicide attempters compared to suicide ideators suggests white matter pathology in TRD and suicide attempt. The effect of free water correction on diffusion metrics and the elevation of free water itself provide evidence toward the source of anisotropic changes. Future investigations to explore the combined impact of these measures in suicide and depression are recommended.

Atrophy of the corpus callosum (CC) is a documented consequence of moderate-to-severe traumatic brain injury (TBI), which has been expressed as volume loss using quantitative magnetic resonance imaging (MRI). Other advanced imaging modalities such as diffusion tensor imaging (DTI) have also detected white matter microstructural alteration following TBI in the CC. The manner and degree to which macrostructural changes such as volume and microstructural changes develop over time following pediatric TBI and their relation to a measure of processing speed is the focus of this longitudinal investigation. As such, DTI and volumetric changes of the CC in participants with TBI and a comparison group at approximately three and 18 months post injury and their relation to processing speed were determined.

Diagnosing diffuse liver disease first involves measurement of blood enzymes followed by biopsy. However, blood markers lack spatial and diagnostic specificity and biopsy is highly risky and variable. Although structural changes have been evaluated using diffusion weighted imaging (DWI), the technique is minimally quantitative. Quantitative MR diffusion approaches, such as intra-voxel incoherent motion (IVIM) and diffusion tensor imaging (DTI) have been proposed to better characterize diseased liver. However, the so called pseudo-hepatic artefact due to cardiac motion, drastically affects DWI results. The overall goals of this thesis were thus to evaluate the pseudo-hepatic anisotropy artefact on the quality of diffusion tensor (DT) and IVIM metrics, and to identify potential solutions. Intra- and intersession DTI repeatability was evaluated in healthy human livers when varying the number of diffusion encoding gradients (NGD) and number of signal averages (NSA). Although no further advantage was observed with increasing NGD beyond 6 directions, increased NSA improved intra- and inter-session repeatability. The pseudo-hepatic artefact resulted in increased fractional anisotropy (FA) and tensor eigenvalues (λ1, λ2, λ3), most prominent in the left liver lobe during systole of the cardiac cycle. Without taking advantage of tensor directional information, increasing the acquired NGD slightly improved IVIM fit quality thus helping to minimize the pseudo-hepatic artefact. Combining IVIM and DTI resulted in FA values closer to the hypothesized value of 0.0, which, based on liver microstructure is most logical. Although both IVIM-DTI and DTI-IVIM exhibited similar fit R2 values, the latter failed more often, especially near major blood vessels. Thus, IVIM-DTI was concluded to be more robust and thus the better approach. / Thesis / Doctor of Philosophy (PhD)

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Diffusion of water molecules in biological tissues depends on several microstructural properties. Therefore, diffusion Magnetic Resonance Imaging (dMRI) is a useful tool to infer and study microstructural brain changes in the context of human development, ageing and neuropathology. In this thesis, the state-of-the-art of advanced dMRI techniques is explored and strategies to overcome or reduce its pitfalls are developed and validated. Firstly, it is shown that PCA denoising and Gibbs artefact suppression algorithms provide an optimal compromise between increased precision of diffusion measures and the loss of tissue's diffusion non-Gaussian information. Secondly, the spatial information provided by the diffusion kurtosis imaging (DKI) technique is explored and used to resolve crossing fibres and generalize diffusion measures to cases not limited to well-aligned white matter fibres. Thirdly, as an alternative to diffusion microstructural modelling techniques such as the neurite orientation dispersion and density imaging (NODDI), it is shown that spherical deconvolution techniques can be used to characterize fibre crossing and dispersion simultaneously. Fourthly, free water volume fraction estimates provided by the free water diffusion tensor imaging (fwDTI) are shown to be useful to detect and remove voxels corrupted by cerebrospinal fluid (CSF) partial volume effects. Finally, dMRI techniques are applied to the diffusion data from the large collaborative Cambridge Centre for Ageing and Neuroscience (CamCAN) study. From these data, the inference provided by diffusion anisotropy measures on maturation and degeneration processes is shown to be biased by age-related changes of fibre organization. Inconsistencies of previous NODDI ageing studies are also revealed to be associated with the different age ranges covered. The CamCAN data is also processed using a novel non-Gaussian diffusion characterization technique which is invariant to different fibre configurations. Results show that this technique can provide indices specific to axonal water fraction which can be linked to age-related fibre density changes.

Long-term cosmic-ray modulation studies using ab initio numerical modulation models require an understanding of the solar-cycle dependence of the heliospheric diffusion tensor. Such an understanding requires information as to possible solar-cycle dependences of various basic turbulence quantities. In this study, 1-minute resolution data for the N-component of the heliospheric magnetic field spanning from 1974 to 2012 is analysed using second-order structure functions constructed assuming a simple three-stage power-law frequency spectrum. This spectrum is motivated observationally and theoretically, and has an inertial, an energycontaining and a cutoff-range at small frequencies to ensure a finite energy density. Of the turbulence quantities calculated from 27-day averaged second-order structure functions, only the magnetic variance and the spectral level show a significant solar-cycle dependence, much less so the spectral index in the energy range. The spectral indices in the inertial range, as well as the turnover and cutoff scales do not appear to depend on the level of solar activity. The ratio of the variance to the square of the magnetic field also appears to be solar-cycle independent. These results suggest that the dominant change in the spectrum over several solar-cycles is its level. Comparisons of the results found in this study with relevant published observations of turbulence quantities are very favourable. Furthermore, when the magnetic variances and heliospheric magnetic magnitudes calculated in this study are used as inputs for theoretically motivated expressions for the mean free paths and turbulence-reduced drift lengthscale, clear solar-cycle dependencies in these quantities are seen. Values for the diffusion and drift lengthscales during the recent unusual solar minimum are found to be significantly higher than during previous solar minima. / MSc (Space Physics), North-West University, Potchefstroom Campus, 2015

Long-term cosmic-ray modulation studies using ab initio numerical modulation models require an understanding of the solar-cycle dependence of the heliospheric diffusion tensor. Such an understanding requires information as to possible solar-cycle dependences of various basic turbulence quantities. In this study, 1-minute resolution data for the N-component of the heliospheric magnetic field spanning from 1974 to 2012 is analysed using second-order structure functions constructed assuming a simple three-stage power-law frequency spectrum. This spectrum is motivated observationally and theoretically, and has an inertial, an energycontaining and a cutoff-range at small frequencies to ensure a finite energy density. Of the turbulence quantities calculated from 27-day averaged second-order structure functions, only the magnetic variance and the spectral level show a significant solar-cycle dependence, much less so the spectral index in the energy range. The spectral indices in the inertial range, as well as the turnover and cutoff scales do not appear to depend on the level of solar activity. The ratio of the variance to the square of the magnetic field also appears to be solar-cycle independent. These results suggest that the dominant change in the spectrum over several solar-cycles is its level. Comparisons of the results found in this study with relevant published observations of turbulence quantities are very favourable. Furthermore, when the magnetic variances and heliospheric magnetic magnitudes calculated in this study are used as inputs for theoretically motivated expressions for the mean free paths and turbulence-reduced drift lengthscale, clear solar-cycle dependencies in these quantities are seen. Values for the diffusion and drift lengthscales during the recent unusual solar minimum are found to be significantly higher than during previous solar minima. / MSc (Space Physics), North-West University, Potchefstroom Campus, 2015

Bipolar disorder is a heritable psychiatric disorder, and several of the genes associated with bipolar disorder and related psychotic disorders are involved in the development and maintenance of white matter in the brain. Patients with bipolar disorder have an increased incidence of white matter hyper-intensities, and quantitative brain imaging studies collectively indicate subtle decreases in white matter density and integrity in bipolar patients. This suggests that genetic vulnerability to psychosis may manifest itself as reduced white matter integrity, and that white matter integrity is an endophenotype of bipolar disorder. This thesis comprises a series of studies designed to test the role of white matter in genetic risk to bipolar disorder by analysis of diffusion tensor imaging (DTI) data in the Bipolar Family Study. Various established analysis methods for DTI, including whole-brain voxel-based statistics, tract-based spatial statistics (TBSS) and probabilistic neighbourhood tractography, were applied with fractional anisotropy (FA) as the outcome measure. Widespread but subtle white matter integrity reductions were found in unaffected relatives of patients with bipolar disorder, whilst more localised reductions were associated with cyclothymic temperament. Next, the relation of white matter to four of the most prominent psychosis candidate genes, NRG1, ErbB4, DISC1 and ZNF804A, was investigated. A core haplotype in NRG1, and three of the four key single nucleotide polymorphisms (SNPs) within it, showed an association with FA in the anterior thalamic radiations and the uncinate fasciculi. For the three SNPs considered in ErbB4, results were inconclusive, but this was consistent with the background literature. Most notable however, was a clear association of a non-synonymous DISC1 SNP, Ser704Cys, with FA extending over most of the white matter in the TBSS and voxel-based analyses. Finally, FA was not associated with a genome-wide supported risk SNP in ZNF804A, a finding which could not be attributed to a lack of statistical power, and which contradicts a strong, but previously untested hypothesis. Whilst the above results need corroboration from independent studies, other studies are needed to address the cellular and molecular basis of these findings. Overall, this work provides strong support for the role of white matter integrity in genetic vulnerability to bipolar disorder and the wider psychosis spectrum and encourages its future use as an endophenotype.

published_or_final_version / Electrical and Electronic Engineering / Master / Master of Philosophy